Mutations in the X-linked gene that encodes MeCP2 (MECP2) are the cause of Rett Syndrome in girls. MECP2 duplication syndrome is an X-linked genomic disorder that accounts for 1-2% of all cases of X-linked intellectual disability (ID), primarily in boys. It is characterized by recurrent respiratory infections, infantile hypotonia, ID progressive neurological declines, and poor to absent speech. Data suggest that there are two distinct clinical paths in this syndrome. One path affects an estimated 50% of the population and is characterized by a dramatic loss of motor skills (regression) that eventually leads to death before the age of 25 resulting from complications of recurrent lower respiratory infections, suggesting possible immune deficits. In contrast, the other path is milder and includes individuals who maintain their milestones and have fewer infections. No study has examined the basis for these two alternative disease paths, or the contributing factors that lead toward a path of decline. The consequence of sustained alterations in biomarkers post-regression has not been examined but is critical to study because it may further increase susceptibility to respiratory infections and complications that lead to early death. The age of regression onset varies between 3-16 years. In addition to specific clinical markers, we have recently discovered that there are immune markers associated with regression that may account for the high frequency of respiratory infections, including impaired functioning of Th1 cells that make the cytokine interferon gamma (IFN-?), and lower vaccine titers. We have also found that decreased activity of the hypothalamic-pituitary-adrenal (HPA) axis (a marker of stress) is associated with regression. This application therefore proposes a longitudinal study consisting of three annual evaluations of the clinical, immune, and stress markers of regression in males between the ages of 3-15 years with MECP2 duplication syndrome. The specific aims are: 1) To determine whether increased respiratory infections, lower cognition, seizures, and increased social withdrawal are associated with regression status, and b) whether clinical markers continue to worsen post-regression, 2) To determine whether lower IFN- production by T helper type 1 cells (TH1) and lower influenza vaccine titers is associated with regression status, and 3) To determine whether HPA axis hypoactivity is associated with regression status. Completion of this study will immediately affect clinical practice through implementation of better guidelines fo yearly vaccines, and guidelines for possible immune therapy. It will also lay the foundation for a future treatment study testing whether drugs known to improve functioning of TH1 cells normalize or improve clinical course, enhance HPA axis activity, and therefore improve quality of life. Finally, completion of our aims will also have broader public health significance for autoimmune disorders consistently associated with MeCP2 overexpression, including: lupus, Sjgren's syndrome, and rheumatoid arthritis.